This proposal is for funds to purchase a 300kV FEC liquid helium cryo-electron microscope for single particle analysis. Cryo-electron microscopy (cryo-EM) has emerged as a powerful approach for visualizing the structures of macromolecular assemblies. Two technological advances, the field emission gun (FEG) electron source and a liquid helium-cooled specimen stage, provide the potential of atomic, or near atomic, resolution. Several ongoing NIH-funded biomedical research projects will benefit greatly from access to a liquid helium cryo-microscope. These include imaging of adenovirus vectors and adenovirus-receptor complexes; DNA-dependent protein kinase (DNA-PK) DNA double-strand break repair complexes; and wild-type and knock-out mouse vaults and recombinant vault-like particles. The vault is a ubiquitous and highly conserved cellular component that has a role in multidrug resistance in cancer cells. The new microscope will ultimately be housed in the California NanoSystems Institute (CSNI) Court of Sciences building at UCLA, which is in the architectural planning phase and is scheduled for completion in 2004. A temporary location for the requested microscope has been identified and evaluated by the FEI Company in the Crump Institute for Molecular Imaging at UCLA, adjacent to UCLA's current 120kV liquid nitrogen cryo-electron microscope. The CNSI seeks to foster interdisciplinary interactions between researchers in the UCLA School of Medicine, College of Letters and Science, School of Engineering, and between UCLA and UC Santa Barbara. Imaging at the molecular, cellular, and organismal levels is an important facet of the CNSI. The CNSI is one of three research efforts selected to receive $100 million in support from the state of California. Nearly 30 corporate partners have already pledged support for the CNSI. If the liquid helium cryo-microscope is funded, CNSI will seek a corporate partner, such as a pharmaceutical company, to help fund the long term operating costs of the microscope. The financial plan for the long term operation of the microscope includes a significant additional commitment from UCLA for microscope operating expenses.